Trastuzumab + Alpelisib +/- Fulvestrant vs Trastuzumab + CT in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer (ALPHABET)

Patients will be excluded from the study if they meet any of the following criteria:

1. Have received more than 5 previous lines of anti-HER2 based therapy for MBC, or prior fulvestrant.

2. Symptomatic visceral disease or any disease burden that makes the patient ineligible for experimental therapy per the investigator's best judgment.

3. Symptomatic central nervous system (CNS) metastases. However, patients with CNS metastases who have been adequately treated, are asymptomatic and do not require corticosteroid or anti-epileptic medication are eligible.

4. Presence of leptomeningeal carcinomatosis.

5. Other invasive malignancy (different from the current breast cancer) at the time of enrollment or previous diagnosis of a completely removed malignancy within 3 years prior to randomization except for adequately treated (including complete surgical removal) of International Federation of Gynecology and Obstetrics (FIGO) stage I grade 1 endometrial cancer, basal or squamous cell carcinoma of the skin, thyroid cancer limited to thyroid gland, in situ carcinoma of the cervix, and grade 1-2 early stage bladder cancer defined as T1 or less, without nodal involvement (N0).

6. Patients with an established diagnosis of diabetes mellitus type I or not controlled type II (FPG ≥ 140 mg/dL \[7.7 mmol/L\] or HbA1c ≥ 6.5%), or history of gestational diabetes (as per American College of Obstetricians and Gynecologists (ACOG) guidelines) or documented steroid-induced diabetes mellitus.

7. Prior treatment with any mTOR, AKT or PI3K inhibitor.

8. Patients treated within the last 7 days prior to treatment initiation with:

* Drugs that are strong inducers of CYP3A4.

* Drugs that are inhibitors of Breast Cancer Resistance Protein (BCRP).

9. Patients who received before randomization:

* Any investigational agent within 4 weeks.

* Chemotherapy within a period of time that is shorter than the cycle duration used for that treatment (e.g. \< 3 weeks for fluorouracil, doxorubicine, epirubicin or \< 1 week for weekly chemotherapy).

* Biologic therapy (e.g., antibodies, other than trastuzumab which is permitted): within 4 weeks prior to starting study treatment.

* Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2 weeks prior to starting study treatment.

* Corticosteroids within 2 weeks prior to starting study treatment. Note: the following uses of corticosteroids are permitted at any time: single doses, topical applications(e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).

* Major surgery or other anti-cancer therapy not previously specified within 4 weeks prior to starting study treatment, (all acute toxic effects, including peripheral neurotoxicity must be resolved to NCI-CTCAE version 5.0 grade ≤ 1, except toxicities not considered a safety risk for the patient at the investigator´s discretion).

10. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following:

* History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis or myocardial infarction within 6 months of randomization.

* History of documented congestive heart failure (New York Heart Association functional classification III-IV).

* Clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place).

* Uncontrolled hypertension defined by a Systolic Blood Pressure ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening.

* Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) \> 470msec.

* Bradycardia (heart rate \< 50 at rest), by electrocardiogram (ECG) or pulse.

* Inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF \> 460 msec for females (using Fridericia's correction). All as determined by screening ECG.

11. Bleeding diathesis (i.e., Disseminated Intravascular Coagulation (DIC), clotting factor deficiency) or long-term (\> 6 months) anticoagulant therapy, other than antiplatelet therapy and low dose coumarin derivatives, provided that the International Normalised Ratio (INR) is less than 1.5.

12. History of clinically significant bowel disease including abdominal fistula, or gastrointestinal perforation.

13. Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active inflammatory bowel disease (e.g., ulcerative diseases).

14. Known hypersensitivity to trastuzumab, alpelisib or fulvestrant or any of their excipients. If known hypersensitivity to either vinorelbine, capecitabine, eribulin or any of their excipients, patient will be eligible as long as the investigator's choice avoids that drug in the control arm.

If known hypersensitivity to all three cytostatics (vinorelbine, capecitabine and eribulin), the patient will not be eligible.

15. Known positive serology for Human Immunodeficiency Virus (HIV), or active infection for hepatitis B or hepatitis C.

16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

17. Patients with currently documented pneumonitis/interstitial lung disease (the chest Computed Tomography \[CT\] scan performed at screening for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).

18. Patient with liver disease with a Child Pugh score B or C.

19. Patient with a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.

20. Patient has a history of Steven-Johnson-Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN).

21. Patient is nursing (lactating) or is pregnant as confirmed by a positive serum human Chorionic Gonadotropin (hCG) test prior to initiating study treatment.

22. Patient is a woman of child-bearing potential or a partner of a woman of child-bearing potential, unless agreement to remain abstinent or use single or combined non-hormonal contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 7 months after the last dose of study treatment, except for patients receiving fulvestrant in which this period should be of at least 2 years.

* Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient.

* Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.

* Examples of non-hormonal contraceptive methods with a failure rate of \< 1% per year include tubal ligation, male sterilization (only if he is the sole partner and have been performed at least 6 months prior to screening), and certain intrauterine devices.

* Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of \< 1% per year. Barrier methods must always be supplemented with the use of a spermicide.

* Male participants must not donate sperm during study and up to the time period specified above.

What this study is about